Pre-clinical Vaccine Development for Respiratory Viruses

呼吸道病毒临床前疫苗开发

• 批准号: 10712583
• 负责人: Richard A Koup
• 金额: $ 248.09万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712583
• 关键词: Animals; Antigens; Chimeric Proteins; Cryoelectron Microscopy; Elderly; Engineering; Glycoproteins; Human; Immunocompromised Host; Individual; Infection; Modification; Mus; Mutation; Newborn Infant; Para-Influenza Virus Type 1; Paramyxovirus; Pneumovirus; Publishing; Rhesus; Structure; Surface; Vaccines; base; burden of illness; design; human pathogen; immunogenicity; nanoparticle; nonhuman primate; pathogen; pre-clinical; respiratory; respiratory virus; response; vaccine candidate; vaccine development; vaccine immunogenicity; vaccine response

Human paramyxoviruses and pneumoviruses are widespread pathogens, cause considerable disease burden. Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. Based on a cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, we engineered in additional mutations different from our previous published modifications in each of the four PIV fusion (F) glycoproteins to further stabilize their metastable prefusion states. The vaccine candidates were able to elicit murine PIV type-specific response, with little cross-neutralization of other PIVs. We evaluated the neutralization responses of the vaccine candidates in nonhuman primates (NHPs). We applied similar concept and designs to hMPV F proteins. In the past year, we designed various mutations to further stabilize the PIV F prefusion trimers and hMPV prefusion trimers. In addition, we designed expression the modified trimers on the surface of different nanoparticles as vaccine immunogens. We are now trying to evaluate the antigenicity of the modified trimers and we selected the most stable ones for mice and NHP animal immunogenicity study. The animal studies are actively going on.

人类帕托病毒和肺炎病毒是广泛的病原体，会导致疾病负担。 1-4型副磷氟糖病毒是高度感染性的人类病原体，其中PIV3最常见于新生儿，老年人和免疫功能低下的个体中严重呼吸道疾病。基于工程PIV3 F预融合稳定的三聚体的冷冻电子显微镜结构，我们采用了与以前在四种PIV融合（F）糖蛋白中的每一种中进行的其他突变进行了设计，以进一步稳定其稳定的预性疗程。候选疫苗能够引起鼠PIV特异性反应，而其他PIV的交叉中和化很少。我们评估了非人类灵长类动物（NHP）中疫苗候选物的中和反应。 我们将类似的概念和设计应用于HMPV F蛋白。在过去的一年中，我们设计了各种突变，以进一步稳定PIV F预选三聚体和HMPV预灌注三聚体。此外，我们将不同纳米颗粒表面的修饰三聚体设计为疫苗免疫原。 我们现在正在尝试评估改良三聚体的抗原性，并为小鼠和NHP动物免疫原性研究选择了最稳定的抗原性。动物研究正在积极进行。